The activity of neurons in both the central and peripheral nervous system is affected by a large number of neuropeptides and neurohormones that act upon cells quite distant from their site of release. Neuropeptides perform many functions in the central nervous system (CNS) as neurotransmitters, neuromodulators, and neurotrophic factors. Neurohormones can modify the ability of nerve cells to respond to synaptic neurotransmitters.
Morphine and its phamacoanalogs bind selectively at many recognition sites throughout the body to produce pharmacologic effects. Brain loci involved in the transmission of pain and in the alteration of reactivity to painful stimuli appear to be the primary, but not the only sites, at which opiods act. In general, sites that display a high affinity for exogenous opioid ligands also contain high concentrations of several endogenous peptides having opioid-like properties. These peptides have been named endorphins and are derived from larger precursor proteins. The peptide precursor molecules for the endorphins are present at brain sites that have been implicated in pain modulation and also in many other tissues. Although endorphins share many features in chemistry and pharmacology, they possess distinct differences with respect to their biochemical and neuronal pathways. For example, they can be activated during stress such as that produced by pain or the anticipation of pain.
Activation of endorphins results in their interaction with cell surface receptors of the CNS. Both endogenous and exogenous opioids can produce opioid receptor mediated analgesia at sites outside the CNS. This analgesic action may occur because mu (.mu.), kappa (.kappa.), and delta (.delta.) receptors located on primary afferent neurons are activated. A fourth receptor, the sigma (.sigma.) receptor, is more controversial but may be related to the dysphoric, hallucinogenic, and cardiac stimulant effects of opioids.
The .sigma. binding sites have preferential affinity for the dextrorotary isomers of certain opiate benzomorphans, such as (+)SKF 10047, (+)cyclazocine, and (+)pentazocine and also for some narcoleptics such as haloperidol. The .sigma. receptor has at least two subtypes, which may be discriminated by stereoselective isomers of these pharmacoactive drugs. SKF 10047 has nanomolar affinity for .sigma.1 site, and has micromolar affinity for the .sigma.2 site. Haloperidol has similar affinities for both subtypes. Endogenous .sigma. ligands are not known, although progesterone has been suggested to be one of them. Possible .sigma.-site-mediated drug effects include modulation of glutamate receptor function, neurotransmitter response, neuroprotection, behavior, and cognition (Quirion, R. et al. (1992) Trends Pharmacol. Sci. 13:85-86). Most studies have implied that .sigma. binding sites (receptors) are plasmalemmal elements of the signal transduction cascade. Drugs reported to be selective .sigma. ligands have been evaluated as antipsychotics (Hanner, M. et al. (1996) Proc. Natl. Acad. Sci. 93:8072-8077).
The cDNA encoding the .sigma..sub.1 receptor has recently been isolated from guinea pig liver. Northern blot analysis showed that highest densities of .sigma..sub.1 mRNA were present in brain, liver, kidney, stomach, jejunum, placenta, ovary, and adrenal gland. The tissue distribution was in agreement with its proposed participation in sterol synthesis. Comparisons with coding sequences from other organisms indicated that the guinea pig .sigma..sub.1 binding site of the receptor was similar to a fungal sterol isomerase (Hanner et al. (supra)).
Physiological data have suggested that the .sigma..sub.1 receptor plays an important role in hippocampal function (Monnet, F. P. et al. (1994) Br. J. Pharmacol. 112:709-715). Sigma ligands potentiate the NMDA-induced excitation of CA3 pyramidal cell neurons in rat dorsal hippocampus. The effects upon hippocampal neurons are differentially affected by pertussis toxin (Monnet et al. (supra)). The existence of .sigma. receptors in the CNS, immune, and endocrine systems have suggested a likelihood that it may serve as a link between the three systems. However, lack of a highly selective .sigma. ligand has hampered efforts to understand the possible physiological roles of (.sigma. receptors (Su. T.-P. (1991) Eur. J. Biochem. 200:633-642).
The discovery of a new human sigma receptor and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of vesicle trafficking, immunological, and neoplastic disorders.